Annotation of fine-mapping results using methylation sumary stats

1 Preliminaries

1.1 Include

library(biovizBase)
library(ggbio)

library(FDb.InfiniumMethylation.hg19)

Known genes:

library(TxDb.Hsapiens.UCSC.hg19.knownGene)
txdb <- TxDb.Hsapiens.UCSC.hg19.knownGene 

library(EnsDb.Hsapiens.v75)
ensdb <- EnsDb.Hsapiens.v75 

library(SNPlocs.Hsapiens.dbSNP144.GRCh37)
snpdb <- SNPlocs.Hsapiens.dbSNP144.GRCh37

1.2 Settings

options(copdgene_ver_acs = 2)

1.3 Varibales

traits_cont <- copdgene_traits_main()[-1]
traits_bin <- copdgene_traits_main()[1]
traits_all <- c(traits_bin, traits_cont)

1.4 Association results

Single-trait asosciationr results:

tab1 <- copdgene_results_admixed(traits_cont, "SmokCigNow", 
  "~/git/hemostat/copdgene/results/07-scan-ver-4/rdata/")
tab2 <- copdgene_results_admixed(traits_cont, "SmokCigNow0_15", 
  "~/git/hemostat/copdgene/results/07-scan-ver-4/rdata/")

Multi-trait asosciationr results:

massoc1 <- readRDS(file.path(
  "~/git/hemostat/copdgene/results/07-scan-ver-4",
  "rdata/massoc.interaction.SmokCigNow.rds"))
massoc2 <- readRDS(file.path(
  "~/git/hemostat/copdgene/results/07-scan-ver-4",
  "rdata/massoc.interaction.SmokCigNow0_15.rds"))

2 Methylation summary stats

Article Genetically contextual effects of smoking on genome wide DNA methylation, 2017, Am J Med Genet B Neuropsychiatr Genet.

Data description

• 2,567 inidviduals (of the 5,125 inidividuals in total) have the methylation data measured in blood
• (clean) 484,241 CpG methylation sites measured by the Illumina HumanMethylation450 BeadChip
• (clean) 403,192 SNPs

Results

Analysis	Tests	Significant	Proprotion	BF Threshold
Smoking effects	484,125	525	0.108%	1e-7
Interaction effects	126,369,511	827	0.0065%	3.96e-10
Interaction effects	195,068,554,297	448,242	0.00023%	2.60e-13

• 1M window for cis-effects. Otherwise, trans-effects.
• The outcome is methylation

3 Chr 11, PARVA gene (interaction with SmokCigNow)

3.1 Manhattan plots

3.2 Fine-mapping

chr <- 11
start <- 12e6
end <- 13e6

gr1 <- GRanges("chr11", IRanges(start, end)) %>% range(ignore.strand = TRUE)

Table of top 10 SNPs:

rank	snp	zscore	pval	chr	pos	acs	num_snps	size	trait
1	rs933920	2.928	0.003413	11	12,481,110	chr11acs76906	21	36,273	FEV1pp_utah
2	rs4553350	-2.847	0.004407	11	12,759,834	chr11acs76938	29	164,946	FEV1pp_utah
3	rs11022386	2.788	0.005301	11	12,548,017	chr11acs76922	2	2,166	FEV1pp_utah
4	rs6485989	2.719	0.006554	11	12,695,171	chr11acs76938	29	164,946	FEV1pp_utah
5	rs1564947	2.633	0.008467	11	12,176,409	chr11acs76843	24	23,173	FEV1pp_utah
6	rs4756884	-2.557	0.01055	11	12,474,098	chr11acs76906	21	36,273	FEV1pp_utah
7	rs901291	-2.528	0.01146	11	12,205,793	chr11acs76851	4	3,812	FEV1pp_utah
8	rs7131034	-2.499	0.01247	11	12,183,036	chr11acs76844	3	576	FEV1pp_utah
9	rs10831908	-2.452	0.0142	11	12,812,419	chr11acs76938	29	164,946	FEV1pp_utah
10	rs3812760	2.447	0.0144	11	12,557,016	chr11acs76925	21	25,500	FEV1pp_utah

Table of top 10 SNPs of top ancesty segment (chr11acs76906):

rank	snp	zscore	pval	chr	pos	acs	num_snps	size	trait
1	rs933920	2.928	0.003413	11	12,481,110	chr11acs76906	21	36,273	FEV1pp_utah
6	rs4756884	-2.557	0.01055	11	12,474,098	chr11acs76906	21	36,273	FEV1pp_utah
11	rs4756866	-2.369	0.01781	11	12,448,846	chr11acs76906	21	36,273	FEV1pp_utah
23	rs10831815	2.076	0.03792	11	12,446,924	chr11acs76906	21	36,273	FEV1pp_utah
24	rs10741590	2.056	0.03976	11	12,463,318	chr11acs76906	21	36,273	FEV1pp_utah
31	rs1344615	-1.901	0.05725	11	12,454,046	chr11acs76906	21	36,273	FEV1pp_utah
53	rs11022358	1.647	0.09951	11	12,470,449	chr11acs76906	21	36,273	FEV1pp_utah
59	rs10831827	-1.603	0.1089	11	12,483,197	chr11acs76906	21	36,273	FEV1pp_utah
63	rs1365403	1.571	0.1161	11	12,476,231	chr11acs76906	21	36,273	FEV1pp_utah
67	rs1346220	1.543	0.1229	11	12,480,087	chr11acs76906	21	36,273	FEV1pp_utah

Gene model tracks:

List of genes: DKK3, MICAL2, MICALCL, PARVA, TEAD1.

Methylation tracks:

3.2.1 Meth. with cis SNP-by-smoking effects

CpG	SNP	Beta	p-value	Methylation Gene
cg20233228	rs16911103	-4.258	4.41e-13	TEAD1
cg20233228	rs16911106	-4.165	1.58e-12	TEAD1

Positions of meth. probes:

CpG	probeStart	probeEnd
cg20233228	12903562	12903611

Positions of SNPs in COPDGene dataset:

CpG	SNP	chr	pos
cg20233228	rs16911103	NA	NA
cg20233228	rs16911106	NA	NA

Positions of SNPs in SNPdb:

CpG	SNP	chr	pos
cg20233228	rs16911103	11	12,343,740
cg20233228	rs16911106	11	12,344,805

3.2.2 Meth. with trans SNP-by-smoking effects

10 (out of 167) rows with the largest effect sizes:

CpG	SNP	Beta	p-value
cg25413748	rs658709	-516.9	NA
cg13569714	rs10840730	-278.1	NA
cg20233228	rs2175132	-12.58	NA
cg20233228	rs17036909	-12.56	NA
cg20233228	rs1396797	-12.49	NA
cg20233228	rs1396795	-12.49	NA
cg20233228	rs7953537	-12.21	NA
cg20233228	rs17094401	-12.21	NA
cg20233228	rs17094405	-12.2	NA
cg20233228	rs17094560	-12.16	NA

Positions of meth. probes:

CpG	probeStart	probeEnd
cg13569714	12,033,074	12,033,123
cg25413748	12,437,801	12,437,850
cg08647724	12,479,811	12,479,860
cg23384960	12,626,522	12,626,571
cg20233228	12,903,562	12,903,611

Positions of SNPs (top 10 effect sizes) in SNPdb:

CpG	SNP	chr	pos
cg25413748	rs658709	20	3,587,400
cg13569714	rs10840730	12	17,662,085
cg20233228	rs2175132	2	69,887,369
cg20233228	rs17036909	2	69,883,592
cg20233228	rs1396797	2	69,872,657
cg20233228	rs1396795	2	69,872,562
cg20233228	rs7953537	12	44,693,288
cg20233228	rs17094401	12	44,696,784
cg20233228	rs17094405	12	44,700,415
cg20233228	rs17094560	12	44,769,768

4 Correlations among predictors for Ancestry and SNPs

   ---   orthogonalizing from global acs. 

Reading /Users/andreyziyatdinov/git/hemostat/copdgene/procdata/finemap/gdat2_chr11.rds 
Reading /Users/andreyziyatdinov/git/hemostat/copdgene/procdata/finemap/gdat2_chr11.bed 

5 Chr 2, TWIST2 gene (interaction with SmokCigNow0_15)

5.1 Manhattan plots

5.2 Fine-mapping

chr <- 2
start <- 237.75e6
end <- 239e6
end2 <- 240e6

gr2 <- GRanges("chr2", IRanges(start, end)) %>% range(ignore.strand = TRUE)

Table of top 10 SNPs:

rank	snp	zscore	pval	chr	pos	acs	num_snps	size	trait
1	rs7597880	-2.801	0.005097	2	2.38e+08	chr2acs210672	2	84	FVC_utah
2	rs12613388	-2.759	0.005791	2	238,660,169	chr2acs210750	3	3,957	FVC_utah
3	rs3739051	-2.616	0.008892	2	2.39e+08	chr2acs210780	1	0	FVC_utah
4	rs2280289	2.369	0.01786	2	238,483,729	chr2acs210712	21	56,543	FVC_utah
5	rs7597414	-2.264	0.02359	2	2.38e+08	chr2acs210671	1	0	FVC_utah
6	rs2701336	2.261	0.02375	2	237,906,903	chr2acs210664	1	0	FVC_utah
7	rs2279642	-2.228	0.02591	2	238,682,770	chr2acs210753	21	97,602	FVC_utah
8	rs6431563	2.223	0.02621	2	238,804,355	chr2acs210764	1	0	FVC_utah
9	rs2701337	-2.218	0.02659	2	237,909,007	chr2acs210665	1	0	FVC_utah
10	rs10187629	-2.211	0.02701	2	238,640,263	chr2acs210747	2	1,258	FVC_utah

Table of top 10 SNPs of top ancesty segment (chr2acs210712):

rank	snp	zscore	pval	chr	pos	acs	num_snps	size	trait
4	rs2280289	2.369	0.01786	2	238,483,729	chr2acs210712	21	56,543	FVC_utah
31	rs7598559	1.683	0.09237	2	238,435,398	chr2acs210712	21	56,543	FVC_utah
42	rs13394555	1.548	0.1217	2	238,483,322	chr2acs210712	21	56,543	FVC_utah
56	rs10190103	1.338	0.181	2	238,482,636	chr2acs210712	21	56,543	FVC_utah
114	rs2325814	-0.9431	0.3456	2	238,462,725	chr2acs210712	21	56,543	FVC_utah
124	rs6705903	-0.9155	0.3599	2	238,433,955	chr2acs210712	21	56,543	FVC_utah
125	rs2292881	0.9096	0.363	2	238,434,249	chr2acs210712	21	56,543	FVC_utah
151	rs2292877	-0.7854	0.4322	2	238,458,180	chr2acs210712	21	56,543	FVC_utah
154	rs1979763	-0.781	0.4348	2	238,436,481	chr2acs210712	21	56,543	FVC_utah
159	rs6766	0.7544	0.4506	2	238,483,164	chr2acs210712	21	56,543	FVC_utah

Gene model tracks:

List of genes: COL6A3, COPS8, LRRFIP1, MLPH, PRLH, RAB17, RAMP1, RBM44, SCLY, UBE2F, UBE2F-SCLY.

Methylation tracks:

5.3 Where is TWIST2?

List of (sorted) genes: ASB1, COL6A3, COPS8, ESPNL, HDAC4, HES6, ILKAP, KLHL30, LINC01107, LINC01940, LOC151174, LRRFIP1, MIR4440, MLPH, PER2, PRLH, RAB17, RAMP1, RBM44, SCLY, TRAF3IP1, TWIST2, UBE2F, UBE2F-SCLY.